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dc.contributor.authorBarrera-Vilarmau, Susana-
dc.contributor.authorObregón, Patricia-
dc.contributor.authorAlba, Eva de-
dc.date.accessioned2012-06-14T09:09:06Z-
dc.date.available2012-06-14T09:09:06Z-
dc.date.issued2011-06-23-
dc.identifier.citationPLoS One 6(6):e21413(2011)es_ES
dc.identifier.issn1932-6203-
dc.identifier.urihttp://hdl.handle.net/10261/51535-
dc.description13 páginas, 9 figuras, 4 figuras S, 2 tablas Ses_ES
dc.description.abstractHarakiri is a BH3-only member of the Bcl-2 family that localizes in membranes and induces cell death by binding to prosurvival Bcl-xL and Bcl-2. The cytosolic domain of Harakiri is largely disorder with residual α-helical conformation according to previous structural studies. As these helical structures could play an important role in Harakiri's function, we have used NMR and circular dichroism to fully characterize them at the residue-atomic level. In addition, we report structural studies on a peptide fragment spanning Harakiri's C-terminal hydrophobic sequence, which potentially operates as a transmembrane domain. We initially checked by enzyme immunoassays and NMR that peptides encompassing different lengths of the cytosolic domain are functional as they bind Bcl-xL and Bcl-2. The structural data in water indicate that the α-helical conformation is restricted to a 25-residue segment comprising the BH3 domain. However, structure calculation was precluded because of insufficient NMR restraints. To bypass this problem we used alcohol-water mixture to increase structure population and confirmed by NMR that the conformation in both milieus is equivalent. The resulting three-dimensional structure closely resembles that of peptides encompassing the BH3 domain of BH3-only members in complex with their prosurvival partners, suggesting that preformed structural elements in the disordered protein are central to binding. In contrast, the transmembrane domain forms in micelles a monomeric α-helix with a population close to 100%. Its three-dimensional structure here reported reveals features that explain its function as membrane anchor. Altogether these results are used to propose a tentative structural model of how Harakiri workses_ES
dc.description.sponsorshipThis work was supported by the European Commission Marie Curie International Reintegration Grant (IRG-046412 to E.d.A.), by the Spanish Ministerio de Ciencia e Innovación through the Programa Ramón y Cajal to E.d.A., by Plan Nacional I+D+i (grant BFU2008-03278 to E.d.A.), by Comunidad de Madrid and Agencia CSIC IV PRICIT (grant CCG08-CSIC/SAL-3777 to E.d.A.), and by the Spanish Ministerio de Ciencia e Innovación through the Consolider-Ingenio 2010 program (grant CSD2009-00088). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscriptes_ES
dc.language.isoenges_ES
dc.publisherPublic Library of Sciencees_ES
dc.relation.isversionofPublisher’s version-
dc.rightsopenAccesses_ES
dc.titleIntrinsic Order and Disorder in the Bcl-2 Member Harakiri: Insights into its Proapoptotic Activityes_ES
dc.typeartículoes_ES
dc.identifier.doi10.1371/journal.pone.0021413-
dc.description.peerreviewedPeer reviewedes_ES
dc.relation.publisherversionhttp://dx.doi.org/10.1371/journal.pone.0021413es_ES
dc.identifier.e-issn1932-6203-
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